Gonadal steroid hormones play an important role in central nervous system development, including brain areas associated with cognition. High levels of progestin binding and progestin receptor (PR) mRNA have been reported in developing cortex, at around the time when the cortex synthesizes high levels of progesterone de novo. Peak levels of PR expression are concurrent with many major growth processes, such as peak dendritic spine and afferent synapse formation in cortical neurons. We used the cellular-level resolution of immunohistochemistry to characterize changes in PR expression within specific cortical lamina over the course of development. The results indicate that PR immunoreactivity (PR-ir) is transiently expressed in specific lamina of frontal, parietal, temporal and occipital cortex. Beginning on E18, PR-ir was observed in subplate cells and then in increasingly superficial lamina (primarily lamina V, then II/III) as postnatal development continued through P13. By P27, this pattern of PR-ir was absent. Double labeling with specific antibodies indicated that PR-ir colocalized with microtubule associated protein (MAP)-2, a neuronal marker, but not with the glial marker, nestin, nor with GABA-ir, suggesting that PR is primarily expressed in excitatory neurons. We also examined whether PR function alters dendritic branching and spine formation on developing cortical cells. Rat pups were subcutaneously injected with the PR antagonist RU486 or oil daily and then sacrificed on P6, P11 or P14. Immunohistochemistry and Western immunoblots were used to measure the levels of synaptic (synaptophysin, syntaxin, spinophilin) and dendritic protein (MAP-2). No differences were found between RU486 and vehicle treated pups in any brain areas examined. These results suggest that specific subpopulations of cortical neurons may be transiently sensitive to progesterone, and that progesterone and its receptor may play a critical role in the fundamental mechanisms underlying normal cortical perinatal development. However, PR influence on perinatal development may exclude effects on cortical synaptogenesis and dendrite formation.

Recent anatomical and neurochemical studies suggest that the dorsal raphe nucleus (DRN) of the brainstem is composed of several subdivisions that have different afferent and efferent connections and are different neurochemically. In the present study, DRN subdivisions projecting to visual system structures were studied in a highly visual rodent, the Mongolian gerbil (Meriones unguiculatus). In one group of gerbils, the fluorescent neural tract tracer Fluoro-Gold was injected into the superior colliculus (SC), and brain sections also were double-labeled for serotonin (5-hydroxytryptamine, 5-HT). In another group of gerbils, the neural tract tracer cholera toxin subunit B (CTB) was injected into the SC, lateral geniculate nucleus (LGN), or primary visual cortex (V1). The location of retrogradely labeled cells in the DRN was analyzed at five rostro-caudal levels to determine DRN subdivisions projecting to these visual structures. At the three most rostral coronal levels, virtually all cells projecting to the SC occurred in the lateral DRN; most of these cells were serotonergic. At these rostral levels, virtually all cells projecting to the LGN also were observed in the lateral DRN. At the two most caudal levels, retrogradely labeled cells were observed in the ventromedial and interfascicular DRN following tracer injections into the SC or LGN. Following CTB injections into the primary visual cortex, virtually all retrogradely labeled cells occurred in the ventromedial DRN at all rostro-caudal levels. Therefore, the ventral caudal region of the DRN appeared to be the only DRN region projecting to all three visual areas (SC, LGN, and V1). In order to determine whether functional differences might exist among DRN subdivisions, the expression of c-fos, an immediate-early gene, was analyzed in all DRN subdivisions throughout the light-dark cycle. In all subdivisions, the highest c-Fos expression was observed one hour after the onset of the dark period. However, ANOVA analysis revealed that the diurnal variation in c-Fos expression was statistically significant only in the caudal ventral region of the DRN, and gradually became less prominent in the caudal-to-rostral and ventral-to-dorsal directions. A portion of this Dissertation has been previously published in the Journal of Comparative Neurology (Janušonis et al., 1999).

There are two parts to the thesis: a simulation system and a model of the anuran retina. The simulation system, called MDL for Model Development Language, uses an assignment statement notation tailored for 2-dimensional layered neural networks. The key features are: (1) Operations occur on 2-dimensional arrays which correspond to the layout of many brain structures. (2) A spatial convolution operation models spatial summation occurring in dendritic trees. (3) Time invariant expressions and differential equations are specified in a manner that removes the numerical methods from the model. These features allow high level modeling using leaky integrator model neurons and modeling of detailed biophysical properties, such as the Hodgkin Huxley equations and voltage clamp experiments. Conciseness of the language allows specification of a moderately complex retina model in only one or two pages. The retina model consists of models for each of the five major anuran ganglion cell types. A common model OPL (Outer Plexiform Layer) containing receptors, horizontals, and bipolar cells generates input to the model Inner Plexiform layer (IPL). Processing in the IPL specific to each ganglion cell type forms the model which qualitatively accounts for many characteristic ganglion cell response properties. The class 2, 3, and 4 cell models also quantitatively account for response dependence on extent and orientation of moving rectangular stimuli and dependence on stimulus velocity. The model shows that horizontal cells are not crucial for most receptive field properties, but may control sensitivity of bipolar cells in a way that prevents class 1 and class 2 cells from responding to full field illumination changes. For class 1, 3, and 4 cells, a simple weighted summation of bipolar cell and differentiated bipolar cell outputs is sufficient to explain responses, although in the class 3 cell, the onset of inhibition must be delayed with respect to excitation. The class 2 cell model requires a more complex means of summing IPL inputs to account for erasability and neuronal adaptation. Differences in transient amacrine cells feeding to each ganglion cell type may underlie variation in velocity dependence. The model yields suggestions for future experiments and modeling.

Pseudoneglect (PN) reveals a contralateral bias in the deployment of visuospatial attention by the dominant (right) hemisphere. The magnitude of PN is phasically modulated by transient exogenous visual cues which automatically recruit attention to cued locations. Optimal cue-line onset asynchrony (SOA), cue-contrast of this cueing effect and the relative effectiveness of cue locations relative to line endpoints are unknown. Similarly, the direction of line scanning modulates the tonic bias, although the origin of this modulation is unknown. The present experiments aim at informing theories about visuospatial attention as well as some neurological conditions such as hemispatial neglect. Four experiments were conducted where observers performed a tachistoscopic visual line bisection task. In experiments 1-3, pretransected lines were preceded by peripheral cues delivered to the left and right line ends at a variety of (1) stimulus onset asynchronies (SOAs), (2) contrasts and (3) horizontal positions relative to the line endpoints. Experiment 4 used a tachistoscopic line bisection protocol to manipulate the type (saccadic, smooth pursuit) and direction (leftward, rightward) of attentional scanning, executed with or without eye movements (overt, covert) while performing eye-tracking. Experiment 1 demonstrated early attentional capture with optimal cue-line SOA of 60 ms. Experiment 2 demonstrated that cue contrasts below 12% were ineffective in modulating perceived midpoint and the maximal effect occurred for cues of 100% contrast. Experiment 3 demonstrated modulation of the spatial error resulting from cues at all locations except the one lying completely beyond the line endpoints. Experiment 4 showed that leftward scanning resulted in leftward error and rightward scanning resulted in rightward error. Smooth pursuit scanning was more potent than saccadic scanning. Overt scanning was more potent than covert scanning and overall the strongest effects were found in leftward overt smooth pursuit scanning. Results from the cueing experiments suggest that the mechanisms subserving exogenous attentional capture in line bisection are fast, predominantly parvocellular-mediated and exert their effects at least partially in an object-referenced coordinate system. Experiment 4 suggests attentional magnification of the left line halve where visuospatial attention is deployed asymmetrically ahead of a scanned target.

Cerebral palsy (CP) is the most common cause of physical disability in childhood. Today, most children with CP survive into adulthood with life expectancies similar to typically developing (TD) adults. One of the biggest challenges during the lifespan of individuals with CP is healthy aging; to prevent or minimize the secondary effects of CP on the musculoskeletal system (e.g. bone deformities due to spasticity) as well as to improve functional status and quality of life. There is currently no treatment that is able to cure the brain damage which causes CP, but a variety of options exist to address spasticity, the most prevalent primary condition which is estimated to be present in 80% of people with CP. One of these options is the neurosurgical procedure of Selective Dorsal Rhizotomy (SDR) which entails selective sectioning of dorsal rootlets in the lumbosacral area, diminishing spasticity through reducing muscle tone. SDR gained increasing acceptance following the work of Peacock and Arens in the 1980s, and although a large number of studies have demonstrated the benefits of this procedure, they largely comprise relatively short-term follow-up assessments in children and adolescents. There is thus a need for long-term follow-up studies focussed on all facets of daily living (International Classification of Function, Disability and Health (ICF) model domains: body structure and function, activity and participation) and quality of life in adults with CP who underwent SDR in their childhood. The aim of this doctoral thesis was to address this need, and provide information that might help guide parents, caregivers and clinicians in their clinical decision-making process for a child with CP. This aim was addressed through three key investigations. First, the status of adults with CP and spastic diplegia - related to all domains of the ICF-model and health-related quality of life - was determined more than 25 years after SDR. Second, changes in gait pattern, spinal deformities and level of activities and participation in adults with CP were determined nine years after a similar assessment. Third, associations between results in the different ICFmodel domains along with personal and environmental context factors. This PhD thesis forms part of a longitudinal investigation tracking the health and wellness of adults with CP. The former studies were performed in 2008 and consequently a recent follow-up was conducted in 2017 in the same CP cohort. All participants underwent SDR according to the Peacock method (strict selection criteria were adhered) at Red Cross War Memorial Children’s Hospital in Cape Town, South Africa, between 1981 and 1991. This PhD thesis is based on four studies, with the first being a cross-sectional study conducted in 2017 (Chapter 2) and the other three are nine-year follow-up studies (comparing findings in 2017 with studies conducted in 2008 (Chapter 3 - 5). Each study included a matched TD group, except for the spine study (Chapter 4). Participants were observed and assessed for functioning, health, disability and quality of life based on a physical examination, gait analysis, functional mobility tests, spine radiographs and several questionnaires. With respect to the ICF-model Body structure and function domain, adults with CP showed sustained reduction in muscle tone and minimal signs of spasticity in their gait pattern, with no increased prevalence of scoliosis, hyperkyphosis or hyperlordosis, and did not experience limitation of daily activities due to pain. Some challenges were found regarding ROM, muscle strength, selectivity and back pain but they were comparable with what would be expected in adults with CP who did not undergo SDR. Concerning, the Activity domain, the majority of the cohort was independent in functional mobility and the accomplishment of daily activities with no increased risk for falls. They were as satisfied with accomplishing daily activities as the TD adults, though as might be expected, they were found to be less content with their level of mobility. Regarding Participation domain, the adults with CP greater than 25 years post-SDR were independent and satisfied with their attainment of social roles. Most were married or had a relationship, lived independently (with or without partner), finished higher education and were engaged in paid employment. The perceived health-related quality of life was similar to that of TD adults in most of the health concepts (physical role functioning, bodily pain, general health, vitality, social functioning, emotional role functioning and mental health), except for physical functioning. No increased prevalence of anxiety and depression was found, which was in line with the reported mental health findings of the health-related quality of life questionnaire. This suggests that while adults with CP have on-going physical challenges following SDR, this might not directly impact their mental health and levels of anxiety and depression. The majority of the cohort viewed the SDR they had undergone as worthwhile due to mobility and functional walking gains. Importantly, no changes were found over the nine-year interval in overall gait, functional mobility, spinal deformities, pain and level of accomplishment and satisfaction in daily activities and social participation. This indicates stability of function which is remarkable since functional decline might be expected in adults with CP while aging. However, correlations were found between functional mobility and daily activities and social participation as well as between functional mobility and strength. This highlights the possible importance of resistance training and maintaining walking ability to enable daily activities and social participation and prevent functional deterioration in the future.

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